chr16-1220449-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021098.3(CACNA1H):c.6517C>T(p.Pro2173Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,540,922 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 2 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.246

Publications

5 publications found

Variant links:

Genes affected

CACNA1H (HGNC:1395): (calcium voltage-gated channel subunit alpha1 H) This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]

CACNA1H Gene-Disease associations (from GenCC):

hyperaldosteronism, familial, type IV
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
childhood absence epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
epilepsy, childhood absence, susceptibility to, 6
Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

CACNA1H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014710844).

BP6

Variant 16-1220449-C-T is Benign according to our data. Variant chr16-1220449-C-T is described in ClinVar as Benign. ClinVar VariationId is 529664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000276 (42/152262) while in subpopulation EAS AF = 0.00503 (26/5168). AF 95% confidence interval is 0.00352. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.6517C>T	p.Pro2173Ser	missense_variant	Exon 35 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.6517C>T	p.Pro2173Ser	missense_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.6532C>T	p.Pro2178Ser	missense_variant	Exon 34 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.6502C>T	p.Pro2168Ser	missense_variant	Exon 34 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.6499C>T	p.Pro2167Ser	missense_variant	Exon 34 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.6499C>T	p.Pro2167Ser	missense_variant	Exon 35 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.6484C>T	p.Pro2162Ser	missense_variant	Exon 35 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.6478C>T	p.Pro2160Ser	missense_variant	Exon 35 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.6466C>T	p.Pro2156Ser	missense_variant	Exon 34 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.6460C>T	p.Pro2154Ser	missense_variant	Exon 34 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.6410C>T	p.Pro2137Leu	missense_variant	Exon 36 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.6359C>T	p.Pro2120Leu	missense_variant	Exon 35 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.6332C>T	p.Pro2111Leu	missense_variant	Exon 36 of 36			ENSP00000518768.1
CACNA1H	ENST00000637236.3 link	n.*2436C>T		non_coding_transcript_exon_variant	Exon 34 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*1565C>T		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*4335C>T		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*5961C>T		non_coding_transcript_exon_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*1458C>T		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*1376C>T		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*2096C>T		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*1184C>T		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*1151C>T		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.*431C>T		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.6517C>T		non_coding_transcript_exon_variant	Exon 35 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.6484C>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*1633C>T		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000711483.1 link	c.*431C>T		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.*431C>T		3_prime_UTR_variant	Exon 34 of 34			ENSP00000518769.1
CACNA1H	ENST00000637236.3 link	n.*2436C>T		3_prime_UTR_variant	Exon 34 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*1565C>T		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*4335C>T		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*5961C>T		3_prime_UTR_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*1458C>T		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*1376C>T		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*2096C>T		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*1184C>T		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*1151C>T		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.*431C>T		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711488.1 link	n.*1633C>T		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000621827.2 link	n.6121+396C>T		intron_variant	Intron 35 of 36	6		ENSP00000518766.1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00502

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000561

AC:

AN:

167512

AF XY:

0.000390

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000744

Gnomad EAS exome

AF:

0.00494

Gnomad FIN exome

AF:

0.000595

Gnomad NFE exome

AF:

0.0000384

Gnomad OTH exome

AF:

0.000261

GnomAD4 exome

AF:

0.000151

AC:

209

AN:

1388660

Hom.:

Cov.:

AF XY:

0.000156

AC XY:

107

AN XY:

686454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30020

American (AMR)

AF:

0.00

AC:

AN:

30046

Ashkenazi Jewish (ASJ)

AF:

0.000429

AC:

AN:

20996

East Asian (EAS)

AF:

0.00369

AC:

143

AN:

38708

South Asian (SAS)

AF:

0.000122

AC:

AN:

73532

European-Finnish (FIN)

AF:

0.000456

AC:

AN:

48272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5376

European-Non Finnish (NFE)

AF:

0.00000922

AC:

AN:

1084582

Other (OTH)

AF:

0.000280

AC:

AN:

57128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000276

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41562

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00503

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000245

Hom.:

Bravo

AF:

0.000268

ExAC

AF:

0.000626

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV

Benign:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 18, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

5.1

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.16

T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.61

T;T;T;.

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

0.0

N;.;.;.

PhyloP100

0.25

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.4

N;.;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.24

T;.;T;T

Sift4G

Benign

0.61

T;.;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.060

MVP

0.27

ClinPred

0.011

GERP RS

2.6

Varity_R

0.042

gMVP

0.069

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over